研究人员表示，核内TDP-43的丢失是TDP-43蛋白病中神经变性的一个标志，包括肌萎缩侧索硬化症（ALS）和额颞叶痴呆症（FTD）。TDP-43错位导致编码stathmin-2（也称为SCG10）的前信使RNA（pre-mRNA）的隐性剪接和多腺苷酸化，这种蛋白质是轴突再生所需的。
研究人员发现，TDP-43与一个富含GU的区域结合，立体地阻断了对STMN2前mRNA中隐性3’剪接位点的识别。靶向dCasRx或反义寡核苷酸（ASO）抑制了隐性剪接，这在TDP-43缺陷的人类运动神经元中恢复了轴突再生和stathmin-2依赖的溶酶体运输。在经过基因编辑的含有人类STMN2隐性剪接聚腺苷酸化序列的小鼠中，ASO注射到脑脊液中，成功地纠正了Stmn2前mRNA的错误处理，并恢复了stathmin-2的表达水平，与TDP-43结合无关。
附：英文原文
Title: Mechanism of STMN2 cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies
Author: Michael W. Baughn, Ze’ev Melamed, Jone López-Erauskin, Melinda S. Beccari, Karen Ling, Aamir Zuberi, Maximilliano Presa, Elena Gonzalo-Gil, Roy Maimon, Sonia Vazquez-Sanchez, Som Chaturvedi, Mariana Bravo-Hernández, Vanessa Taupin, Stephen Moore, Jonathan W. Artates, Eitan Acks, I. Sandra Ndayambaje, Ana R. Agra de Almeida Quadros, Paayman Jafar-nejad, Frank Rigo, C. Frank Bennett, Cathleen Lutz, Clotilde Lagier-Tourenne, Don W. Cleveland
Issue&Volume: 2023-03-17
Abstract: Loss of nuclear TDP-43 is a hallmark of neurodegeneration in TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 mislocalization results in cryptic splicing and polyadenylation of pre–messenger RNAs (pre-mRNAs) encoding stathmin-2 (also known as SCG10), a protein that is required for axonal regeneration. We found that TDP-43 binding to a GU-rich region sterically blocked recognition of the cryptic 3′ splice site in STMN2 pre-mRNA. Targeting dCasRx or antisense oligonucleotides (ASOs) suppressed cryptic splicing, which restored axonal regeneration and stathmin-2–dependent lysosome trafficking in TDP-43–deficient human motor neurons. In mice that were gene-edited to contain human STMN2 cryptic splice-polyadenylation sequences, ASO injection into cerebral spinal fluid successfully corrected Stmn2 pre-mRNA misprocessing and restored stathmin-2 expression levels independently of TDP-43 binding.
DOI: abq5622
Source: https://www.science.org/doi/10.1126/science.abq5622